Project Summary Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and is the result of reduced levels of the RNA-binding protein FMRP. Past work has focused on mRNAs bound by FMRP in adult neurons, revealing a handful of important targets. However, current therapies based on these targets have not proven effective in patients, perhaps because they do not address the entire set of targets that FMR1 regulates in diverse cell types. Therefore, effective therapies designed to cure FXS will require systemic assessment of the FMRP pathway to identify additional co- factors and targets. This project addresses this need by specifically determining whether FMRP functions in the nervous system via a second RNA-binding protein called LIN-28. It will be carried out using the Drosophila model system, an established FXS model that enables rapid assay of sensitive molecular and genetic interactions at cell-type specific resolution in most tissues. Importantly, this system was previously used to reveal that FMRP and LIN28 interact to control the insulin sensitivity of a non-neural population of stem cells, laying the foundation of the current application. Aims 1-3 will assess whether the LIN28/FMRP pathway also operates in the nervous system: neural fmr1 phenotypes affecting neural stem cells (Aim 1), differentiated neurons (Aim 2) and complex adult behaviors (Aim 3) will be screened for any that are suppressed by removal of lin-28. If this pilot analysis indicates that FMRP acts via LIN28 for any of these roles, future work will be proposed to decipher the mechanistic basis of this interaction. The expected outcome is a significant advance in understanding the FMRP pathway in neural cells, paving the way for therapeutic interventions designed to treat the FXS symptoms.